Controlled release dosage form with enhanced pharmacokinetics
The present invention provides a simple and improved dosage form that is capable of providing a controlled release of GABA B receptor agonist contained in the core thereof. The invention also provides methods of administering the dosage form and of treating conditions that are therapeutically responsive to GABA B receptor agonist.
1. An oral extended release dosage form comprising
a) a core comprising 2.5 to 50 mg of arbaclofen (ARBAC), at least two water-swellable excipients, at least one osmotic salt, and at least one binder; and
b) a semipermeable membrane surrounding the core and comprising at least one film-forming cellulose ester; wherein
said at least two water-swellable excipients comprise a combination of cellulose derivative polymer and polyalkylene oxide polymer;
said combination comprises a major portion of said polyalkylene oxide polymer and a minor portion of said cellulose derivative polymer;
said cellulose derivative polymer is selected from the group consisting of hydroxyalkyl alkylcellulose derivative, hydroxyalkylcellulose derivative, and a combination thereof; and
said polyalkylene oxide has a molecular weight of about 1,000,000 or less.
2. The dosage form of claim 1 , wherein the weight ratio of said core to said membrane ranges from about 10:1 to about 15:1 or about 5:1 to about 10:1.
3. The dosage form of claim 1 , wherein the weight ratio of polyalkylene oxide to cellulose derivative is in the range of about 10:1 to about 25:1, about 13:1 to about 17:1 or about 17:1 to about 22:1.
4. The dosage form of claim 1 , wherein the weight ratio of total water swellable polymer to total binder in the core ranges from about 6:1 to about 2:1 or about 5:1 to about 1:1.
5. The dosage form of claim 1 , wherein the osmotic salt is present at a concentration ranging from about 5 to about 45% wt based upon the weight of the uncoated core, or wherein the weight ratio of total water swellable polymer and to osmotic salt is about 1.5:1 to about 1:1.5 or about 0.7:1 to about 1:1.
6. The dosage form of claim 1 , wherein said semipermeable membrane comprises plasticizer and about 80% wt to less than 100% wt of cellulose ester based upon the final weight of said membrane.
7. The dosage form of claim 6 , wherein said cellulose ester is cellulose acetate.
8. The dosage form of claim 7 , wherein said cellulose acetate comprises at least one of the following grades of cellulose acetate:
Cellulose
Hydroxyl Content
Acetyl Content
Acetate
(% by wt.)
(% by wt.)
Viscosity*
Grade 1
8.7
32
2.4
P
Grade 2
3.5
39-40, 39.8
38
P
Grade 3
7-10
30-36
200-280
sec*
Grade 4
3-5
37-43
6-45
sec*
Grade 5
3-5
37-43
100-240
sec*
wherein * indicates determination of viscosity as set forth in ASTM D817 (Formula A) and D1343.
9. The dosage form of claim 8 , wherein a) the cellulose ester comprises 80-100% of cellulose acetate Grade 1, cellulose acetate Grade 3, or a combination thereof; orb) the membrane comprises 0 to less than 10% wt of cellulose acetate Grade 2, 4, or 5, 90-100% wt of cellulose acetate grade 1 or 3, and 1-10% wt of plasticizer.
10. The dosage form of claim 1 , wherein said membrane ruptures from 0.1 to 1.5 hours after exposure of said extended release dosage form to an aqueous environment of use.
11. The dosage form of claim 1 , wherein, after exposure of said extended release dosage form to an aqueous environment of use, said extended release dosage form exhibits a mean 3-phase sigmoidal in vitro release profile as follows under conditions defined in USP <711>, wherein the first phase lasts no more than about 2 hours, the second phase lasts about 4 to 8 hours, and the third phase lasts about 2 hours or more.
12. The dosage form of claim 1 , wherein said extended release dosage form provides a dissolution profile according to any one of the following:
a) about 40% wt to about 80% wt of the ARBAC is released by about six hours, about 55% wt to about 100% wt of the ARBAC is released by about 8 hours, and no less than 70% wt of the ARBAC is released by about 12 hours after placement in an aqueous environment of use or after oral administration;
b) about 50% wt to about 100% wt of the ARBAC is released by about six hours, about 65% wt to about 100% wt of the ARBAC is released by about 8 hours, and no less than 90% wt of the ARBAC is released by about 12 hours after placement in an aqueous environment of use or after oral administration;
c) about 60% wt to about 100% wt of the ARBAC is released by about six hours, about 75% wt to about 100% wt of the ARBAC is released by about 8 hours, and no less than 90% wt of the ARBAC is released by about 10 hours after placement in an aqueous environment of use or after oral administration;
d) about 45% wt to about 85% wt of the ARBAC is released by six hours, about 65% wt to about 100% wt of the ARBAC is released by 8 hours, and no less than 75% wt of the ARBAC is released by 12 hours after placement in an aqueous environment of use or after oral administration;
e) about 50% wt to about 85% wt of the ARBAC is released by six hours, about 70% wt to about 100% wt of the ARBAC is released by 8 hours, and no less than 85% wt of the ARBAC is released by 10 hours after placement in an aqueous environment of use or after oral administration;
f) about 5% wt to about 40% wt of the ARBAC is released by 2 hours, 45% wt to about 85% wt of the ARBAC is released by six hours, about 65% wt to about 100% wt of the ARBAC is released by 8 hours, and no less than 75% wt of the ARBAC is released by 12 hours after placement in an aqueous environment of use or after oral administration;
g) about 10% wt to about 20% wt of the ARBAC is released by 2 hours, about 25% wt to about 50% wt is released by 4 hours, about 60% wt to about 90% wt of the ARBAC is released by 8 hours, and no less than 75% wt of the ARBAC is released by 12 hours after placement in an aqueous environment of use or after oral administration;
h) about 10% wt to about 20% wt of the ARBAC is released by 2 hours, about 25% wt to about 50% wt is released by 4 hours, 60% wt to about 90% wt of the ARBAC is released by 8 hours, and no less than 80% wt of the ARBAC is released by 12 hours after placement in an aqueous environment of use or after oral administration;
i) about 7% wt to about 20% wt of the ARBAC is released by 2 hours, about 25% wt to about 45% wt is released by 4 hours, about 55% wt to about 80% wt of the ARBAC is released by 6 hours, and no less than 70% wt of the ARBAC is released by 8 hours after placement in an aqueous environment of use or after oral administration;
j) no more than about 20% wt of the ARBAC is released by 2 hours, about 20% wt to about 45% wt is released by 4 hours, about 55% wt to about 90% wt of the ARBAC is released by 8 hours, and no less than 80% wt of the ARBAC is released by 12 hours after placement in an aqueous environment of use or after oral administration;
k) no more than about 20% wt of the ARBAC is released by 2 hours, about 30% wt to about 60% wt is released by 4 hours, about 50% wt to about 70% wt of the ARBAC is released by 6 hours, no less than 70% wt of the ARBAC is released by 8 hours and no less than 80% wt of the ARBAC is released by 12 hours after placement in an aqueous environment of use or after oral administration;
l) No more than about 10% wt of the ARBAC is released by 1 hour, no more than about 20% wt of the ARBAC is released by 2 hours, about 30% wt to about 50% wt is released by 4 hours, about 40% wt to about 70% wt of the ARBAC is released by 6 hours, no less than 60% wt of the ARBAC is released by 8 hours and no less than 75% wt of the ARBAC is released by 12 hours after placement in an aqueous environment of use or after oral administration;
m) no more than about 10% wt of the ARBAC is released by 1 hour, no more than about 20% wt of the ARBAC is released by 2 hours, about 30% wt to about 50% wt is released by 4 hours, about 40% wt to about 70% wt of the ARBAC is released by 6 hours, about 60% wt to about 85% wt of the ARBAC is released by 8 hours and no less than 75% wt of the ARBAC is released by 12 hours after placement in an aqueous environment of use or after oral administration;
n) about 70% wt to about 95% wt of the ARBAC is released by six hours, about 80% wt to about 100% wt of the ARBAC is released by 8 hours, and no less than 90% wt of the ARBAC is released by 12 hours; or
o) about 15% wt to about 35% wt of the ARBAC is released by 2 hours, about 50% wt to about 85% wt is released by 4 hours, about 80% wt to about 100% wt of the ARBAC is released by 8 hours, and no less than 90% wt of the ARBAC is released by 12 hours after placement in an aqueous environment of use or after oral administration.
13. The dosage form of claim 1 , wherein said extended release dosage form provides a dissolution profile according to any of the following:
Dissolution (% wt)
Time
Median or
(hr)
mean
Max
Min
0
0
0
0
2
11
20
5
4
35
50
20
6
61
80
40
8
78
100
55
12
88
70
Dissolution (% wt)
Time
Median or
(hr)
mean
Max
Min
0
0
0
0
2
11
20
5
4
35
50
25
6
61
80
45
8
78
100
65
12
88
80
Dissolution (% wt)
Time
Median or
(hr)
mean
Max
Min
0
0
0
0
2
12
20
5
4
40
50
30
6
65
80
50
8
85
100
70
12
95
90
Dissolution (% wt)
Time
Median or
(hr)
mean
Max
Min
0
0
0
0
2
12
20
5
4
42
50
35
6
67
80
55
8
87
100
75
12
97
100
Dissolution (% wt)
Time
Median or
(hr)
mean
Max
Min
0
0
0
0
1
11
15
5
2
20
30
11
4
50
72
35
6
80
100
61
8
100
78
Dissolution (% wt)
Time
Median or
(hr)
mean
Max
Min
0
0
0
0
1
7
10
2
2
15
20
7
4
40
50
25
6
65
85
50
8
85
100
70
10
100
when determined as described herein.
14. The dosage form of claim 1 , wherein said extended release dosage form provides a plasma profile approximating that depicted in FIG. 2 or FIG. 6 .
15. The dosage form of claim 1 , wherein said extended release dosage form provides a dissolution profile approximating that depicted in FIG. 1 or FIG. 5 inclusive of the area defined by minimum and maximum profiles.
16. The dosage form of claim 1 , wherein said extended release dosage form exhibits in vitro dissolution profile approximating any of those depicted in FIG. 5 and exhibits in vivo single dose plasma profile approximating that depicted in FIG. 6 for formulation T2.